The conceptual framework of this proposal is based on the contention that cocaine dependence leads to long term changes in the brain dopamine (DA) system that leave the chronic user in a prolonged state of hypodopaminergia after abstinence. The acoustic startle response (ASR) is a well-characterized subcortical reflex that is modulated by DA activity in the nucleus accumbens, a region important for drug craving. There is a profound diminution of the ASR in cocaine-dependent subjects after brief abstinence that is consistent with a hypodopaminergic state. Preclinical work also indicates a reduction in the ASR after recurrent cocaine administration. Little is known about the exact time course and mechanism by which this abnormality develops. This proposal would test a hypothesis that chronic cocaine dependence causes a persistent state of functional hypodopaminergia that is reflected in profound startle amplitude reduction. The central objectives of this proposal are (1) to characterize this finding with regard to its development and persistence in initial and later phases of cocaine abstinence, (2) to determine whether severity of ASR reduction and failure of the ASR to normalize during prolonged abstinence is a predictor of clinical course, (3) to determine whether ASR reduction is specific to cocaine dependence or generalizable to dependence on other stimulants, and (4) to study ASR in well siblings of cocaine-dependent subjects to determine whether reduced startle amplitude is a marker of a familial (and by inference genetic) vulnerability to develop cocaine dependence. A long-range goal of this project is to understand the course and clinical significance of the association of prolonged cocaine exposure with marked reductions in ASR amplitude, and to refine the subtyping of cocaine-dependent patients based on the severity of this abnormality. Achieving the latter goal could enhance outcome prediction so that tailored treatments may be directed at patients most vulnerable to relapse, given the severe restriction of resources available for treatment of this destructive addiction. [unreadable] [unreadable]